Neural tube defects (NTD) result in devastating and sometimes fatal birth defects, occuring between the 21st and 27th days after conception, a time when many women do not realize they are pregnant (5).
Results of randomized controlled trials have demonstrated 60–100% reductions in NTD cases when women consumed vitamin B9 (folic acid) supplements in addition to a varied diet about one month before and one month after conception (6, 7, 8).
The results of these and other studies prompted many health authorities to recommend that all women capable of becoming pregnant consume 400 micrograms (mcg) of folic acid daily to prevent NTD. The recommendation was made to all women of childbearing age because adequate folic acid must be available very early in pregnancy, and because many pregnancies are unplanned.
Other pregnancy complications
Adequate vitamin B9 (folate) status may also prevent the occurrence of other types of birth defects, such as certain heart defects and limb malformations. However, the support for these findings is not as consistent or clear as support for NTD prevention (9).
Additionally, low levels of dietary folate during pregnancy have been associated with increased risks of premature delivery, low infant birth weights, increased incidence of miscarriage and pregnancy complications like preeclampsia and placental abruption (10).
Thus, it is reasonable to maintain folic acid supplementation throughout pregnancy, even after closure of the neural tube in order to decrease the risk of other problems during pregnancy.
Cardiovascular disease
Homocysteine and cardiovascular disease
The results of more than 80 studies indicate that even moderately elevated levels of homocysteine in the blood increase the risk of cardiovascular diseases (4): an analysis of observational studies on blood homocysteine and vascular disease indicated that a prolonged decrease in blood plasma homocysteine level of only 1 micromole/liter resulted in about a 10% risk reduction (11).
Most research indicates that a plasma homocysteine level below 10 micromoles/liter is associated with a lower risk of cardiovascular disease and a reasonable treatment goal for individuals at high risk (12). However, it is not yet clear whether lowering homocysteine levels will reduce cardiovascular disease risk.
Vitamin B9 and homocysteine
Vitamin B9 (folate)-rich diets have been associated with decreased risk of cardiovascular disease: a study that followed 1,980 Finnish men for ten years found that those who consumed the most dietary folate had a 55% lower risk of an acute coronary event (e.g., ‘myocardial infarction’) when compared with those who consumed the least dietary folate (13).
Increasing vitamin B9 (folate) intake through folate-rich foods or supplements has been found to lower homocysteine levels: a meta-analysis of 25 randomized controlled trials found that supplementation with 0.8 mg folic acid daily maximally reduced plasma homocysteine concentrations; daily doses of 0.2 mg and 0.4 mg folic acid were associated with 60% and 90% reductions respectively in plasma homocysteine (14).
Folic acid has been shown to have the greatest effect in lowering basal levels of homocysteine in the blood when there is no coexisting deficiency of vitamin B12 or vitamin B6.
Although increased vitamin B9 intake has been found to decrease homocysteine levels, it is presently not clear whether increasing folic acid intake results in decreased risk of cardiovascular diseases. However, an analysis of the randomized controlled Heart Outcomes Prevention Evaluation 2 (HOPE 2) involving 5,522 adults with known cardiovascular disease showed that a daily combination of 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12 for five years lowers homocysteine and reduces the risk of overall stroke, but not stroke severity or disability (15).
A meta-analysis of 12 randomized controlled trials, including data from 16,958 individuals with pre-existing cardiovascular or renal disease, found that folic acid supplementation (alone and combined with vitamin B6 and vitamin B12) had no effect on coronary heart disease, stroke, or all-cause mortality despite 13–52% reductions in plasma homocysteine concentrations (16).
A more recent meta-analysis of eight intervention studies in 16,841 individuals found that folic acid supplementation (alone and combined with vitamin B6 and vitamin B12) significantly reduced the risk of stroke by 18%. A greater beneficial effect was seen in those trials with treatment duration of more than 36 months, a decrease in the concentration of homocysteine of more than 20%, and participants with no history of stroke (17).
Possible reasons for the mixed results of the studies include:
- Elevated blood homocysteine levels may be a consequence rather than a cause of cardiovascular disease.
- The duration of the trials published to date (less than five years) may not be sufficient to reverse the hypothesized damage inflicted by elevated blood homocysteine, which is typically persistent (‘chronic’).
- Over-estimation of a possible treatment effect based on earlier epidemiological studies resulted in intervention trials, which may have included far too few individuals to provide a good basis for testing potential effects.
- The introduction of mandatory fortification of food with vitamins in the U.S., Canada and Australia during the 1990s resulted in lower than expected effects of supplementation, which may not have been shown by studies that were too small.
Additional clinical trials should provide a more definitive answer as to whether vitamin B9 (folic acid) is beneficial for the prevention or treatment of heart disease or stroke.
Cancer
As cancer is thought to arise from DNA damage in excess of ongoing DNA repair and/or the inappropriate gene expression, vitamin B9 (folate) intake might positively affect DNA repair and gene expression (2).
While many study results have been inconsistent, others have been more promising. Overall, the role of folate in the possible prevention of cancer provides an example of the complexity of the interactions between genetics and nutrition.
Colorectal cancer
A meta-analysis of seven cohort and nine case-control studies found that vitamin B9 (folate) from foods increases colorectal cancer risk; however, total folate from foods and folic acid supplements was not associated with colorectal cancer risk (18). As the pooled data were highly heterogeneous, the authors stated that dietary fiber or other vitamins could have confounded their results.
Observational studies have found that relatively low folate intake and high alcohol intake, which interferes with the absorption and metabolism of folate (5), are associated with increased incidence of colorectal cancer (19, 20). In a prospective study of more than 45,000 male health professionals, current intake of more than two alcoholic drinks per day doubled the risk of colon cancer. The combination of high alcohol and low folate intake yielded an even greater risk of colon cancer; however, increased alcohol intake in individuals who consumed 650 micrograms (mcg) or more of folate per day was not associated with an increased risk of colon cancer (21).
While dietary vitamin B9 (folate) may be protective against colorectal cancer, high doses of supplemental folic acid may actually accelerate tumor growth in cancer patients: a trial in patients with a history of colorectal adenoma associated supplementation of 1 mg/day folic acid (more than twice the RDA) with a statistical trend for advanced colorectal lesions as well as with a significantly increased risk (more than double) for the presence of three or more colorectal adenomas (22). In this study, folic acid supplementation was also associated with an increased risk of cancers at other sites, primarily the prostate.
As human observational studies on high-dose folate and cancer have reported mixed results, more research is needed to determine the role of high-dose folate in cancer progression.
Breast cancer
Studies investigating whether vitamin B9 (folate) intake affects breast cancer risk have reported mixed results (23).
The results of two prospective studies suggest that increased folate intake may reduce the risk of breast cancer in women who regularly consume alcohol (24, 25, 26); moderate alcohol intake has been associated with increased risk of breast cancer in women in several studies.
Interestingly, a very large prospective study in more than 88,000 nurses reported that folic acid intake was not associated with breast cancer in women who consumed less than one alcoholic drink per day. However, in women consuming at least one alcoholic drink per day, vitamin B9 (folic acid) intake of at least 600 micrograms (mcg) daily resulted in about half the risk of breast cancer compared with women who consumed less than 300 mcg folic acid daily (26).
Alzheimer's disease and cognitive impairment
The role of vitamin B9 (folate) in nucleic acid synthesis and ‘methylation reactions’ (see Health Functions) is essential for normal brain function. Several investigators have described associations between decreased folate levels and cognitive impairment in the elderly (27).
A large cross-sectional study in elderly Canadians found that those individuals with low serum folate levels were more likely to have dementia, be institutionalized, and be depressed. However, these findings could reflect the poorer nutritional status of institutionalized elderly and individuals with dementia. A study in 30 elderly nuns, who lived in the same convent, ate the same diet, and had similar lifestyles, reported a strong association between decreased blood folate levels and the severity of brain atrophy related to Alzheimer's disease (28).
More recent studies have reported conflicting results as to whether folate status impacts Alzheimer's disease risk (29, 30, 31).
Moderately increased homocysteine levels, as well as decreased vitamin B9 (folate) and vitamin B12 levels, have been associated with Alzheimer's disease and vascular dementia: one study in 370 elderly men and women, who were followed over three years, associated low serum levels of vitamin B12 (below 150 picomoles (pmol)/L) or vitamin B9 (below 10 nanomoles (nmo)l/L) with a doubling in the risk of developing Alzheimer's disease (32). In a sample of 1,092 men and women without dementia followed for an average of ten years, those with higher plasma homocysteine levels at baseline (above 14 micromoles/liter) had a significantly higher (doubled) risk of developing Alzheimer's disease and other types of dementia (33).